Individualized Administration Of Valproic Acid Based On Therapeutic Drug Monitoring

ObjectiveValproic acid(VPA),a first-line broad-spectrum antiepileptic drug,has been widely used in the treatment of seizures and partial seizures as monotherapy or combination therapy.VPA is absorbed rapidly and completely after oral administration.Patients receiving VPA usually have well response.But the application of VPA has encountered several limitations,such as narrow therapeutic range,wide inter-and intra-individual pharmacokinetic variability,high plasma albumin binding ratio and multiple adverse reactions,especially for hepatotoxicity.In order to promote the rational clinical drug use of VPA and reduce the occurrence of adverse reactions,this study investigated the influence of sex,age,dosage and concomitant medication on VPA concentrations in Chinese pediatric inpatients with epilepsy.In addition,since the pharmacokinetic data is generally limiting and the clinical sample size of pediatric patients is small,this study used the Monte Carlo simulation(MCs)to optimize maintenance dosing regimens of VPA and predict the steady-state trough concentration(Cmin SS)and its probabilities to reach the reference ranges in Chinese pediatric patients with epilepsy.Our research coule provide references for the rational clinical drug use of VPAMethod(1)Gender,age,dosage,concomitant medication and serum concentration of VPA in Chinese pediatric patients with epilepsy treated with VPA from May 2018 to July 2018 have been collected,and then analyzed by SPSS 16.0.(2)The population pharmacokinetic parameters including ka,F,Vd,k of VPA treatment for Chinese pediatric patients with epilepsy were obtained from published studies.The predicted steady-state trough concentration(Cmin SS)of VPA for different regimens and its probabilities to reach the reference range 40-100 μg·mL-1 were obtained by MCs.Result(1)Simple linear regression showed that dosage just explained 25%of the variance in serum concentration of VPA.The dose-adjusted VPA serum concentration in female patients were significantly higher than that in male patients(66.28 ± 15.07 and 95.77 ±35.35 μg·mL-1·mg-1·d,respectively).The dose-adjusted VPA serum concentration in elderly patients was(90.38 ± 45.71)μg·mL-1·mg-1.d.It was larger than adult and minor patients,which were(76.63 ± 27.62)and(70.95 ± 21.19)μg·mL-1·mg-1·d,respectively.The co-medication of olanzapine or quetiapine have no significant influence on VPA serum concentrations.(2)Dosing regimens of 11.25 mg·kg-1 bid or 30.00 mg·kg-1 qd in patients>3 years in monotherapy,20.00 mg·kg-1 bid or 65.00 mg·kg-1 qd in patients>3 years co-medicated with carbamazepine,18.75 mg·kg-1 bid or 47.50 mg·kg-1 qd in patients≤3 years in monotherapy,and 20.00 mg·kg-1 bid in patients ≤3 years co-medicated with carbamazepine had the largest probability to reach the reference range of VPA.Conclusion(1)The pharmacokinetics of VPA showed high inter-individual difference and the influential factors of serum drug concentration are complicated.Therefore,therapeutic drug monitoring is recommended regularly.The dosage regimen is suggested to be optimized by therapeutic drug monitoring(TDM)and the clinical effect of patients.(2)Monte Carlo simulation can be used to predict The Cmin SS and its probabilities to reach the reference range in Chinese pediatric patients with epilepsy,which was valuable for optimizing maintenance dosing regimens of VPA.